Sunitinib (compound I) is the international commonly accepted name for N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-yliden)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, and has an empirical formula of C22H27FN4O2, and a molecular weight of 398.47 g/mol. Sunitinib is an active pharmaceutical substance indicated for the treatment of abnormal cell growth, such as cancer, in mammals, particularly in humans.

The malic acid salt of sunitinib has been selected for medical purpose and is commercially marketed under the trade name of SUTENT™ for the treatment of renal cell carcinoma and gastrointestinal stromal tumor.
Sunitinib base and its malate salt are described in U.S. Pat. No. 6,573,293 (“the '293 patent”), which is incorporated herein by reference. In particular, Example 80 of the '293 patent describes the preparation of sunitinib base via condensation of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)amide (compound II) and 5-fluoro-1,3-dihydroindol-2-one (compound III), which may be depicted as in Scheme 1. However, the '293 patent provides no additional details regarding the reaction conditions except a general synthetic procedure elsewhere in the patent.

Example 1 of U.S. Patent Application Publication No. 2007/0191458A1 (“the '458 publication”) describes the preparation of sunitinib malate by reacting sunitinib base with malic acid in the presence of methanol as a solvent (the crystalline form of sunitinib malate obtained has been denominated therein as Form I). The '458 publication is incorporated herein by reference.
Applicants have observed that sunitinib base has a low solubility profile, which makes its dissolution and treatment for the preparation of the corresponding pharmaceutically acceptable salts (e.g., sunitinib malate) cumbersome. In this regard, the low solubility of sunitinib base requires large amounts of solvents or mixture of solvents and/or the use of particular harsh conditions aimed to increase the solubility of sunitinib base and/or reduce long reaction times, which represents a significant drawback, especially for industrial scale-up. Further, solid sunitinib base is difficult to handle since it is a very fine powder which is difficult to filter and isolate.
Thus, there is an unmet need for a process for preparing the malic acid salt of sunitinib which does not require the processing of sunitinib base, and which might be suitable for industrial implementation.